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Low molecular weight heparins including at least one covalent bond with biotin or a biotin derivative, method for making same and use thereof

a low molecular weight, heparin technology, applied in the field can solve the problems of limiting the use conditions, not being able to induce a sufficient regioselectivity, not being able to biotinylate all the functionalizable polysaccharide chains of low molecular weight heparins, etc., to achieve rapid neutralization and reduce the risk of hemorrhage

Inactive Publication Date: 2010-04-01
SANOFI SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]They also have the advantage of being useful in therapeutic indications for which the doses used are higher, while at the same time reducing the risk of hemorrhage; they may thus be useful in the arterial therapeutic field.

Problems solved by technology

However, heparin has drawbacks that limit its conditions of use.
The reason for this is that it is desired to perform the biotinylation on finished products, which are mixtures of heparin-based polysaccharides and are thus heterogeneous products, on which the grafting of biotin as described in the abovementioned patent applications would not make it possible to induce a sufficient regioselectivity of the grafting position and would not allow biotinylation of all the functionalizable polysaccharide chains of low molecular weight heparins.
However, the operating conditions described in the said document do not allow biotinylated heparins to be obtained fully and reproducibly: they do not take into account the structural diversity of heparins and the real structure of the polysaccharide chains as present in the commercially available heparins.
Thus, the operating conditions described in the said publication for the biotinylation of porcine heparin do not allow biotinylated heparins to be obtained fully and reproducibly with expected characteristics, such as a degree of biotinylation sufficient to allow efficient neutralization.

Method used

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  • Low molecular weight heparins including at least one covalent bond with biotin or a biotin derivative, method for making same and use thereof
  • Low molecular weight heparins including at least one covalent bond with biotin or a biotin derivative, method for making same and use thereof
  • Low molecular weight heparins including at least one covalent bond with biotin or a biotin derivative, method for making same and use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

NH LC Biotinoyl Enoxaparin

[0064]Enoxaparin is a low molecular weight heparin obtained according to the process described in U.S. Pat. RE38,743. It is converted into the biotinylated derivative according to the reaction sequence in Scheme 2: enoxaparin is converted via a reductive amination reaction into compound 1 having an amino function at its reducing end, and this derivative is then converted into the biotinylated compound 2 via reaction with 3-sulfosuccinimidyl 6-biotinamido hexanoate, sodium salt.

1.1: 1-Amino Enoxaparin

[0065]1 g of enoxaparin is dissolved in 40 ml of aqueous 5 M ammonium chloride solution. 1 g of sodium cyanoborohydride is added to the solution obtained. The mixture is maintained at 60° C. for 24 hours. The solution is cooled to a temperature in the region of 20° C. and diluted with water (qs 100 ml). The filtrate obtained is desalified on a column of Sephadex G10 and then freeze-dried. 824 mg of a white lyophilizate are obtained. The observed yield is 82%. Th...

example 2

NH Biotinoyl Enoxaparin

[0072]Enoxaparin, a low molecular weight heparin obtained according to the process described in U.S. Pat. RE38,743, is converted into the biotinylated derivative according to the reaction sequence described in Scheme 3: enoxaparin is converted via a reductive amination reaction into compound 1 containing an amino function at its reducing end, and this derivative is then converted into the biotinylated compound 3 via reaction with the biotinoyl-3-sulfosuccinimidyl ester, sodium salt.

[0073]200 mg of 1-amino enoxaparin are dissolved in 5 ml of 0.5 M sodium hydrogen carbonate solution at a temperature in the region of 20° C. 107 mg of sulfo-NHS-biotin are added to the solution obtained. The solution is stirred at a temperature in the region of 20° C. for 1 hour 30 minutes. The suspension obtained is diluted with 10 ml of 0.5 M sodium hydrogen carbonate solution. 107 mg of sulfo-NHS-biotin are added and the mixture obtained is stirred for 3 hours. The reaction medi...

example 3

NH-LC-LC Biotinoyl Enoxaparin

[0079]Enoxaparin, a low molecular weight heparin obtained according to the process described in U.S. Pat. RE38,743, may also be converted into a biotinylated derivative according to the reaction sequence described in scheme 4: enoxaparin is converted via a reductive amination reaction into compound 1 containing an amino function on its reducing end, and this derivative is then converted into the biotinylated compound 4 by reaction with the ester 3-sulfo-succinimidyl 6-biotinamidohexanoyl hexanoate, sodium salt.

[0080]200 mg of 1-amino enoxaparin are dissolved in 5 ml of 0.5 M sodium hydrogen carbonate solution at a temperature in the region of 20° C. 164 mg of sulfo-NHS-LC-LC-biotin are added to the solution obtained. The solution is stirred at a temperature in the region 20° C. for 2 hours. The suspension is diluted with 10 ml of 0.5 M sodium hydrogen carbonate solution. 164 mg of sulfo-NHS-LC-LC-biotin are added and the mixture obtained is stirred for 5...

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Abstract

The invention relates to biotinylated low molecular weight heparins comprising constituent polysaccharides having at their reducing ends at least one covalent bond with biotin or a biotin derivative, and also to the process for preparing them, to pharmaceutical compositions containing them and to their therapeutic use.

Description

FIELD OF THE INVENTION[0001]The present invention relates to low molecular weight heparins, more generally heparinoid-based polysaccharide mixtures, which contain at least one covalent bond with biotin or a biotin derivative, and also to the process for preparing them, to pharmaceutical compositions containing them and to their therapeutic use.BACKGROUND OF THE INVENTION[0002]Heparin is a mixture of sulfated mucopolysaccharides of animal origin, with a molecular weight in the region of 15 000 daltons (Da), used especially for its anticoagulant and antithrombotic properties. However, heparin has drawbacks that limit its conditions of use. In particular, its high anticoagulant activity (especially its high anti-factor IIa activity) may cause hemorrhaging (Seminars in Thrombosis and Hemostasis, vol. 5, sup. 3, 1999).[0003]Low molecular weight heparins between, for example, 3000 and 7000 Da and more particularly between 3500 and 5500 daltons, obtained especially by basic depolymerizatio...

Claims

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Application Information

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IPC IPC(8): A61K31/727C07H1/00
CPCC08B37/0075A61K31/715A61P25/28A61P43/00A61P7/02A61P7/04A61P9/00A61P9/10C08B37/00
Inventor VISKOV, CHRISTIANHUBERT, PHILIPPEMOURIER, PIERRE
Owner SANOFI SA
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